I. PATHOGNESIS OF CEREBRAL ISCHEMIA: The discovery of ET-1 and NO has greatly contributed to our understanding of the functional changes of many organs under physiological and pathological conditions (e.g., hypertension, atherosclerosis, and stroke). In the brain, the endothelium is the main producer of ET-1 and NO, although both of these substances are produced by a variety of cellular elements (e.g., smooth muscle, glia, and neurons). Endothelial ET-1 was shown to induce NO secretion that, in turn, reduced the production of ET-1. These reactions, which are mediated by ETA and ETB receptors, contribute to the maintenance of vascular tone and control of circulation (e.g., cerebral blood flow and blood pressure) as well as blood-brain barrier function. The regulatory mechanisms involved in this interplay have recently been shown to involve Ca2+ mobilization, cytoskeletal (actin and vimentin) rearrangements and vasodilator-stimulated phosphoprotein changes that are mediated by c-GMP/c-GMP kinase system. Recently studies focused on interactions of endocannabinoids [2-arachidonoylglycerol (2-AG) and anandamide (ANA)] with the vasoconstrictor, endothelin-1 (ET-1). Both 2-AG and ANA are produced in various organs (brain, gut) and cells [monocytes, platelets, endothelial cells (EC)]; they elicit neuromodulatory,cytoprotective ( i.e. brain ischemia and trauma )and cardiovascular effects, which are mediated through cannabinoid (CB) receptors CB1, CB2 or vanilloid (VRA1) receptors. Current research analyzes the cytoprotective properties and distinct mechanisms involved in the modulation of endothelial responses by these substances. Changes in the Ca2+ levels and the cytoskeleton rearrangements in cerebral vascular EC implicate the active participation of CB1 receptors in EC function and possibly cerebral vascular disease processes. These findings implicate 2-AG/ET-1 interactions in cerebral capillary and microvascular endothelial responses and provide a potential alternative pathway for abrogating ET-1-inducible microvascular effects in the brain. Most recently, we also have investigated the possible role of nitroxides in ameliorating postischemic hypoperfusion. All of these findings may prove useful in devising a multifactorial strategy for the treatment of cerebral ischemia. II. TOLERANCE TO CEREBRAL ISCHEMIA: The study of SHR-SP tolerization with E-selectin (in collaboration with Dr. J. Hallenbeck) demonstrated a reduced incidence and size of brain infarct and hemorrhage. Continued investigation is focused on the mechamism responsible for these events. In addition, a new initiative for stroke prevention (induction of mucosal tolerance to E-selectin) involves a preclinical study with spontaneously hypertensive, genetically stroke-prone rats and an approved Phase II A Clinical Trial